The physico-chemical characteristics of medicaments play a critical role in determining the range of their potential applications. Hydrophobic medicaments, for example, but may require appropriate formulation for use in a hydrophilic biological environment.
In the case of photosensitizing drugs, the majority of them that are of pharmaceutical interest for photodynamic therapy (PDT) are based on the tetra- or polypyrrolic structure, which are hydrophobic in character. Their effectiveness relies on their association with cellular membranes, thereby being able to target highly sensitive membranous intracellular organelles that control critical metabolic functions. The hydrophobic character of the photosensitizers means that they cannot be administered directly to a hydrophilic environment due to a tendency to aggregate (by molecular stacking, precipitation or other mechanisms), which can severely curtail photosensitization processes (Siggel et al. J. Phys. Chem. 100(12):2070-2075, December 1996). Thus they require formulation in carriers which are able to provide a hydrophobic environment to maintain them in a non aggregated form in both the formulation and in aqueous preparations prior to use. For photosensitizers such as porphyrin- and benzoporphyrin (green porphyrin) derivatives, the tendency to undergo aggregation has been found to be high.
The photosensitizer benzoporphyrin derivative mono-acid-ring A (BPD-MA, Verteporfin®, QLT PhotoTherapeutics Inc., Vancouver, BC, Canada) has been successfully formulated using liposomes as a carrier. Liposomal preparations containing porphyrin photosensitizers are described in allowed U.S. application Ser. No. 08/489,850 filed Jun. 13, 1995, which is incorporated herein in its entirety by reference. Liposomal BPD-MA was originally manufactured on a large scale using the conventional thin film technique where the drug and lipids are dissolved in a volatile organic solvent in a round bottom flask and deposited as a film as the solvent is removed by rotary evaporation. The film is then hydrated using an iso-osmolar solution of lactose to produce large multilamellar vesicles (MLVs). These undergo a size reduction process using homogenization prior to filter sterilization, packaging and lyophilization to produce a final pharmaceutical product. Both the thin film production and hydration processes were found to be problematic for large scale manufacturing.
An alternative process to thin film suitable for large-scale manufacturing is the “Presome” technology (U.S. Pat. No. 5,096,629). Briefly, the method involves pumping superheated organic solutions of phospholipids into a large evacuated sterile chamber. This process removes the organic solvent and results in lipid powder. The photosensitizer BPD-MA, phospholipids, and antioxidants are dissolved in methylene chloride to produce presome powder. The presome powder is then hydrated using lactose monohydrate solution, followed by microfluidization, filter-sterilization and then lyophilization. In this process, lactose solution has been used as an iso-osmolar agent for hydrating the thin film or presome powder before lyophilization. The presome powder yields a similar final product to that of the conventional thin film method. Therefore presome technology has the advantage of being suitable for large scale production but has similar limitations and numerous step requirements as described for the thin film. Yet another process is based on the formation of a “proliposome” (see U.S. Pat. No. 4,744,989 and WO 87/07502) which could reduce the number of steps in the manufacture of liposomal photosensitizers.
The synthesis of BPD-MA normally results in equimolar quantities of A-ring and B-ring intermediates. The B-ring compounds are effective photosensitizers, but further development for PDT treatment using these compounds has been limited by their greater tendency to undergo self-aggregation and their lower solubility compared to A-ring compounds. Aggregation results in inefficient delivery of drug to plasma proteins on injection into the blood stream and poor performance in vivo. It also poses a greater formulation challenge as B-ring compounds have been shown to undergo aggregation within the bilayer in liposomal formulations. The use of various homopolymeric systems e.g. polyvinylpyrrolidones (PVPs) and polyethylene glycols (PEGs) have also proved unsuccessful in preventing aggregation in B-ring compounds.
Formulations using biocompatible block copolymers are receiving increasingly wider usage in the pharmaceutical industry for enhancing drug solubility and bioavailability (reviewed by Schmolka, Chapter 10, pp189-214, in Tarcha (Ed.) Polymers for Controlled Drug Delivery, CRC Press, Boch Raton, Fla., 1991; Alexandridis & Hatton, Colloids and Surfaces 96:1-46, 1995)). Poloxamers are an example of block copolymers found to be useful in this area. These are symmetrical compounds of the A-B-A type composed of a central PPO (polypropylene oxide) with flanking PEO (polyethylene oxide) blocks on both sides. The PPO block provides the hydrophobic interaction with the drug to be stabilized.
There is a continuing need in the art for alternative formulations and processing methods which will allow the preparation of photosensitizer drug formulations, with a minimum number of steps, and in a form which is suitable for storage, as well as rapid hydration or reconstitution to produce a form suitable for therapeutic use. Preferably, methods should also be amenable to large-scale production.